Imatinib mesylate in the treatment of Core Binding Factor leukemias with KIT mutations: A report of three cases
Introduction
It has been recently documented that the incidence of KIT point mutations ranges from 5% to 40% of newly diagnosed acute myeloid leukemias (AML) with t(8;21) (q22;q22) and inv(16) (p13;q22) [1], [2]. Mutations may affect either the juxtamembrane domain proposed to regulate the activity of an otherwise normal enzymatic site of the KIT receptor, such as insertion or deletions of exon 8 or 11 of the KIT gene, or may affect the structure of the tyrosine kinase domains I and II (kinase domain mutations) as in cases with single amino acid substitution at codon 816 (D816 mutants). These types of mutations lead to a gain-of-function of the KIT receptor and induce a KIT-dependent proliferation. Recently, investigators at the Columbia University reported that Imatinib is able to inhibit KIT-dependent phosphorylation in a human mast cell leukemia cell line subclone (HMC1.1), which expresses only the Val560Gly juxtamembrane mutation, but failed to suppress constitutive phosphorylation of KIT in the HMC1.2 subclone, which expresses both the Val560Gly and kinase mutations (Asp816Val), establishing a general rule whereby classification of mutations may be useful in predicting tumour sensitivity to inhibitory drugs [3].
Aim of the present study is to investigate the capability of Imatinib to induce an anti-leukemic effect in Core Binding Factor (CBF)-leukemia patients presenting either with extracellular juxtamembrane or kinase KIT mutations.
Section snippets
Mutational analysis
Exon 17 mutations in the KIT gene were identified by sequencing and by more sensitive assays as HinfI assay for Asp816Val as previously described [1] and amplification refractory mutation system (ARMS) PCR for Asp816Tyr. Briefly, 168 bp (mutated) ARMS PCR products of KIT exon 17 were generated using the following primers: 17A 5′-AGTTTTCACTCTTTACAAG-3′ and 17B 5′-TTAGAATCATTCTTGATGTA-3′. Denaturing, annealing and extension steps were performed at 94 °C for 30 s, 48 °C for 20 s, 72 °C for 20 s, and a
Patients with KIT kinase mutations
Case no. 1: A 58-year-old woman, with a history of breast cancer, was diagnosed with AML(M4Eo) and D816V KIT mutation on June 2003. After a standard induction chemotherapy (idarubicin and cytarabine), she received two consolidation courses (idarubicin and High Dose-cytarabine; High Dose-cytarabine) but relapsed 3 months thereafter. Treatment with Imatinib was started 8 days after a single dose of cytarabine 100 mg/m2 as continuous infusion and 24 h after hydroxiurea 1500 mg per day orally for 3
Discussion
Complete remission achieved upon administration of Imatinib in the treatment of patients with advanced leukemias has been rarely reported in the recent literature; furthermore, the biological basis of the observed responses remained unknown [5], [6], [7]. Aim of this work was to investigate the capability of Imatinib to induce an anti-leukemic effect in CBF-leukemia patients presenting either with kinase or extracellular juxtamembrane KIT mutations to validate, in vivo, the general paradigm
Acknowledgements
R. Cairoli contributed to the concept and design, interpreted and analyzed the data and provided drafting of the article. A. Beghini contributed to the concept, interpreted and analyzed the data and provided drafting of the article. G. Grillo collected and assembled the data. E. Morello and M. Montillo provided study materials/patients. L. Larizza and E. Morra provided critical revisions and important intellectual content and gave final approval of article.
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Mastocytosis and related disorders
2012, Seminars in Diagnostic PathologyCitation Excerpt :The diagnosis of MML/MM-MDS is then confirmed by the lack of dense mast cell aggregates in the biopsy and the lack of D816V KIT mutation. KIT D816V mutation has also reported to be present in cases of AML with genetic alterations affecting CBF, particularly those associated with t(8;21) translocation involving CBFα, with incidence ranging from 1.7% to 6.9%.74-79 KIT exon 8 mutation has also been found in cases of CBF-AML, particularly inv(16) involving CBFβ.53,80
High frequency of concomitant mastocytosis in patients with acute myeloid leukemia exhibiting the transforming KIT mutation D816V
2010, Molecular OncologyCitation Excerpt :Figure 5 shows serum tryptase levels in various groups of patients with AML. Several reports have suggested that in a group of patients with AML, the transforming mutation KIT D816V is detectable (Cairoli et al., 2005; Nanri et al., 2005; Goemans et al., 2005; Cammenga et al., 2005; Schnittger et al., 2006). This mutation is otherwise found in neoplastic mast cells in patients with SM, but is not detectable in other myeloid neoplasms (Nagata et al., 1995; Longley et al., 1996; Fritsche-Polanz et al., 2001; Feger et al., 2002).
A phase II trial of high-dose imatinib mesylate for relapsed or refractory c-kit positive and Bcr-Abl negative acute myeloid leukaemia: The AFR-15 trial
2009, Leukemia ResearchCitation Excerpt :If the Kit D816 V mutation is already known to confer resistance to imatinib, it remains possible that other mutations could confer anti-leukemic activity to imatinib in the setting of CBF AML [9]. Reports of the use of imatinib in CBF AML (excluding Kit D816 V mutation) have so far shown no efficacy [10]. As none of the patients in our series exhibited CBF AML, conclusions regarding the efficacy of imatinib can only be drawn for c-kit positive and Bcr-Abl and CBF negative AML.